How Do Atrial-Selective Drugs Differ From Antiarrhythmic Drugs Currently Used in the Treatment of Atrial Fibrillation?

Abstract

Current pharmacologic strategies for the management of Atrial fibrillation (AF) include use of 1) sodium channel blockers, which are contraindicated in patients with coronary artery or structural heart disease because of their potent effect to slow conduction in the ventricles, 2) potassium channel blockers, which predispose to acquired long QT and Torsade de Pointes arrhythmias because of their potent effect to prolong ventricular repolarization, and 3) mixed ion channel blockers such as amiodarone, which are associated with multi-organ toxicity. Accordingly, recent studies have focused on agents that selectively affect the atria but not the ventricles. Several Atrial-selective approaches have been proposed for the management of AF, including inhibition of the Atrial-specific ultra rapid delayed rectified potassium current (IKur), acetylcholine-regulated inward rectifying potassium current (IK-ACh), or connexin-40 (Cx40). All three are largely exclusive to atria. Recent studies have proposed that an Atrial-selective depression of sodium channel-dependent parameters with agents such as ranolazine may be an alternative approach capable of effectively suppressing AF without increasing susceptibility to ventricular arrhythmias. Clinical evidence for Cx40 modulation or IK-ACh inhibition are lacking at this time. The available data suggest that Atrial-selective approaches involving a combination of INa, IKur, IKr, and, perhaps, Ito block may be more effective in the management of AF than pure IKur or INa block. The anti-AF efficacy of the Atrial-selective/predominant agents appears to be similar to that of conventionally used anti-AF agents, with the major apparent difference being that the latter are associated with ventricular arrhythmogenesis and extra cardiac toxicity.

Figure 1. Block of I_Kur with 4-aminopyridine (4-AP, 50 μM)

Abbreviates APD₉₀ in “healthy” (plateau-shaped action potential), but prolongs it in “acutely remodeled” (triangular-shaped action potential) canine coronary-per fused Atrial preparations (pectinate muscles). Low flow ischemia was used to generate the “acutely remodeled” atria. Left panel is from Burashnikov et al., with permission.

Figure 2. Ranolazine specifically induces prolongation of the effective refractory period (ERP) and development of post-repolarization refractoriness in atria

(PRR, the difference between ERP and APD₇₅ in atria and between ERP and APD₉₀ in ventricles; ERP corresponds to APD₇₅ in atria and APD₉₀ in ventricles). CL = 500 ms. C – control. The arrows in panel A illustrate the position on the action potential corresponding to the end of the ERP in atria and ventricles and the effect of ranolazine to shift the end of the ERP in atria but not ventricles. * p<0.05 vs. control. † = p<0.05 vs. APD₇₅ values in atria and APD₉₀ in ventricles; (n=5–18). From Burashnikov et al with permission.

Figure 3. Ranolazine produces a much greater rate-dependent inhibition of the maximal action potential upstroke velocity (V_max) in atria than in ventricles

A: Normalized changes in V_max of Atrial and ventricular cardiac preparations paced at a cycle length (CL) of 500 ms. C: Ranolazine prolongs late repolarization in atria, but not ventricles and acceleration of rate leads to elimination of the diastolic interval (during which the recovery from sodium channel block occurs), resulting in a more positive take-off potential in atrium and contributing to Atrial selectivity of ranolazine. The diastolic interval remains relatively long in ventricles. * p<0.05 vs. control. † p<0.05 vs. respective values of M cell and Purkinje (n=7–21). From Burashnikov et al with permission.